Diabetic complications are believed to involve elevated amounts of advanced glycation end products (AGE's) (Vlassara et al., Lab. Invest. 70:138-151, 1994; Jakus et al., Physiol. Res. 53:131-142, 2004). AGE's are formed by the non-enzymatic reaction of amino acids and amino groups of proteins with reducing sugars (Maillard, CR Acad. Sci. 154:66-8, 1912). The AGE's thus formed can eventually cross link with peptides and proteins to form complexes that can lead to diabetic complications (for review see Bucala et al., Adv. Pharmacol. 23:1-34, 1992; Brownlee, Metabolism 49:9-13, 2000; Singh et al., Diabetologia 44:129-146, 2001).
One detectable measure of glycation is the formation of fructose amine on plasma proteins like human serum albumin as well as serum HbA1c, both by the non-enzymatic glycation reaction of hemoglobin with glucose (McDonald et al., J. Biol. Chem. 253:2327-2332, 1978). Both fructose amine and the HbA1c levels in diabetic patients have been shown to reflect mean blood glucose concentration over the previous two weeks to almost four months, thus providing a way of documenting the degree of control of glucose metabolism (Koenig et al., N. Engl. J. Med. 295:417-420, 1976). Of the two indicators, the relationship between HbA1c and plasma glucose has been defined based upon a regression analysis of values observed in a multicenter clinical trial and the relationship has been reported to be useful in diabetes control (Rohlfing et al., Diabetes Care 25:275-8, 2002).
Factors other than glucose have also been reported to influence non-enzymatic glycation including oxygen tension and 2,3-diphosphoglycerate concentrations which is an example of an organic phosphate catalyzed glycation (Smith et al., J. Clin. Invest. 69:1164-1168, 1982). Increasing phosphate concentrations have also been reported to enhance glycation in vitro (Hall et al. Biochimica et Biophysica Acta 993:217-223, 1989; Kunika et al., Life Sci. 45:623-630, 1989; Kunika et al., Diabetes Research and Clinical Practice 17:9-16, 1992). In addition, in non-diabetic healthy humans, inorganic phosphate concentrations have been reported to be significantly correlated to the levels of the glycation product, fructosamine, corrected for glucose concentrations. (Kunika, supra, 1992). The magnitude of protein glycation was estimated in this report from blood glucose concentration and inorganic phosphorus concentration based upon an in vitro rate of glycation (Id.). Nevertheless, the combined role of HbA1c, glucose and inorganic phosphorus concentrations in determining glycemia status in diabetic patients has not been heretofore defined.